Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy with an estimated 22,350 newly diagnosed cases and 10,710 deaths due to MM in the United States in 2013. MM, typically a disease of the elderly, is a malignancy of clonal plasma cells in the bone marrow (BM) characterized by the presence of paraproteinemia, destructive bone disease, hypercalcemia, renal failure, and/or hematological dysfunction. Although survival rates of MM patients have improved by recent therapeutic advances, MM remains incurable due to the persistence of minimal residual disease. Hence, novel modalities complementing or improving current treatment options are desperately needed. There is ample evidence that immunomodulatory drugs are effective against MM. Thus, the use of a potent immunotherapeutic is an attractive approach to provide durable immune responses to or even potentially cure patients with MM. Interleukin-15 (IL-15), a crucial factor for the development, proliferation and activation of effector NK cells and CD8+ memory T cells, exhibits potent anti-tumor activities against well-established tumors in animal models. Based on its properties, IL-15 is considered by NCI as the most promising immunotherapeutic product candidate that could potentially cure cancer. We have previously isolated a novel proprietary IL-15 mutant with increased biological activity. The immunostimulatory properties of this superagonist IL-15 (IL-15N72D) was further improved by creating a complex with an IL-15 receptor - IgG1 fusion protein. We postulate that administration of this complex (referred to as ALT-803) will induce a durable, potent and broad cell-mediated immune response, which could result in efficacious and potentially curative effects in patients with MM. This approach is supported by results of our SBIR Phase I project indicating that ALT-803 indeed eradicated well- established myeloma tumors and prolonged survival of tumor-bearing mice through a novel mechanism dependent on the activation of CD8+ memory T cells and secretion of IFN-y from these T cells. Furthermore, short-term ALT-803 treatment provided long-lasting T cell dependent immunological effects that completely protected mice against subsequent tumor cell rechallenge. These studies provide a strong rationale for advancing ALT-803 into clinical testing against MM as a curative treatment. In addition to the SBIR Phase I project, we have completed animal toxicology studies and manufacture of ALT-803 clinical product allowing FDA acceptance of an IND for clinical use of ALT-803 in other cancer indications. Under this SBIR Phase II proposal, we plan to conduct a multicenter Phase 1/2 study to investigate the safety, pharmacokinetics, and immunostimulatory and clinical activities of ALT-803 in patients with refractory or relapsed MM. Successful completion of this study will pave the way for further evaluation of ALT-803 either as monotherapy or in combination with chemotherapies in patients with relapsed/refractory MM with the ultimate goal of developing more durable or curative therapeutic options for treatment-nave and/or relapsed/refractory MM patients.